Neurobiological Correlates of EMDR Monitoring – An EEGStudyMarco Pagani1*, Giorgio Di Lorenzo2, Anna Rita Verardo3, Giampaolo Nicolais4, Leonardo Monaco2,

Giada Lauretti3, Rita Russo3, Cinzia Niolu2, Massimo Ammaniti5, Isabel Fernandez3, Alberto Siracusano2

1 Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy, 2 Department of Systems Medicine, University of Rome ‘‘Tor

Vergata’’, Rome, Italy, 3 EMDR Italy Association, Bovisio Masciago (MI), Italy, 4 Department of Developmental and Social Psychology, ‘‘Sapienza University of Rome’’, Rome,

Italy, 5 International Psychoanalytical Association, ‘‘Sapienza University of Rome’’, Rome, Italy

Abstract

Background: Eye Movement Desensitization and Reprocessing (EMDR) is a recognized first-line treatment for psychologicaltrauma. However its neurobiological bases have yet to be fully disclosed.

Methods: Electroencephalography (EEG) was used to fully monitor neuronal activation throughout EMDR sessionsincluding the autobiographical script. Ten patients with major psychological trauma were investigated during their firstEMDR session (T0) and during the last one performed after processing the index trauma (T1). Neuropsychological tests wereadministered at the same time. Comparisons were performed between EEGs of patients at T0 and T1 and between EEGs ofpatients and 10 controls who underwent the same EMDR procedure at T0. Connectivity analyses were carried out by laggedphase synchronization.

Results: During bilateral ocular stimulation (BS) of EMDR sessions EEG showed a significantly higher activity on the orbito-frontal, prefrontal and anterior cingulate cortex in patients at T0 shifting towards left temporo-occipital regions at T1. Asimilar trend was found for autobiographical script with a higher firing in fronto-temporal limbic regions at T0 moving toright temporo-occipital cortex at T1. The comparisons between patients and controls confirmed the maximal activation inthe limbic cortex of patients occurring before trauma processing. Connectivity analysis showed decreased pair-wiseinteractions between prefrontal and cingulate cortex during BS in patients as compared to controls and between fusiformgyrus and visual cortex during script listening in patients at T1 as compared to T0. These changes correlated significantlywith those occurring in neuropsychological tests.

Conclusions: The ground-breaking methodology enabled our study to image for the first time the specific activationsassociated with the therapeutic actions typical of EMDR protocol. The findings suggest that traumatic events are processedat cognitive level following successful EMDR therapy, thus supporting the evidence of distinct neurobiological patterns ofbrain activations during BS associated with a significant relief from negative emotional experiences.

Citation: Pagani M, Di Lorenzo G, Verardo AR, Nicolais G, Monaco L, et al. (2012) Neurobiological Correlates of EMDR Monitoring – An EEG Study. PLoS ONE 7(9):e45753. doi:10.1371/journal.pone.0045753

Editor: Ulrike Schmidt, Max Planck Institute of Psychiatry, Germany

Received May 20, 2012; Accepted August 24, 2012; Published September 2 , 2012

Copyright: � 2012 Pagani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors have no support or funding to report.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: marco.pagani@istc.cnr.it

Introduction

Post-traumatic conditions lead to derangement of memory and

mood regulation possibly ending with a fear-driven response

elicited by internal or external cues associated with a traumatic

situation [1].

Investigations by positron emission tomography (PET) and

single photon emission computed tomography (SPECT) have

identified an impairment of the medial prefrontal cortex (mPFC),

associated with a hyper-reactivity of the amygdalae, to constitute

the core neural correlate of post-traumatic stress disorder (PTSD)

[2]. On the other hand, several studies have provided evidence for

the clinical efficacy of Eye Movement Desensitization and

Reprocessing therapy (EMDR) in the treatment of PTSD [3].

EMDR is an information processing therapy for anxiety disorders

that focuses on trauma elaboration or highly stressful recollections

[4]. A distinct characteristic of EMDR is the use of alternating

bilateral stimulation such as eye movement, tactile or auditory.

The patient is asked to focus upon the traumatic memory image

while simultaneously attending to an alternate stimulus for brief

eye movements (right-left) sets of approximately 30 seconds. As a

result EMDR has been included in many international trauma

treatment guidelines [5–8] and in 2011 has also been shortlisted as

evidence-based practice for the treatment of PTSD [9], anxiety

and depression symptoms [10].

Recent studies have probed into EMDR’s mechanism of action

and its physiological and neurobiological substrate [11–15]

providing some preliminary evidence of an association between

functional changes and treatment efficacy. However, none of these

studies succeeded in investigating real-time firing of brain neurons

in response to the external stimuli induced by EMDR since the

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6

effects of therapy on brain activation/deactivation were only

recorded before and after EMDR treatment. This has restricted

the reported information to static conditions not describing in

detail the dynamics of regional neuronal synchronization during

EMDR sessions.

Electroencephalography (EEG) helps to overcome such limiting

factors as it records brain electrical activity with a time resolution

of milliseconds and with an acceptable capability to identify the

sources of activity in the brain 3D space, especially by means of a

medium to high-density array of electrodes [16].

The aim of the study was (i) to explore the technical feasibility of

the on-line recording of whole EMDR sessions by means of EEG;

(ii) to identify the regions activated either by the autobiographic

recollection of the traumatic event (script) or during the bilateral

ocular stimulation at EMDR sessions; (iii) to investigate possible

changes in functional connectivity both as a result of EMDR

therapy or comparing patients and healthy controls; (iv) to

correlate such changes to neuropsychological scores.

Due to the exploratory nature of the present study, we analyzed

and reported separately all activities for the different frequencies of

the cerebral electric spectrum.

Materials and Methods

SubjectsTen psychologically traumatised symptomatic patients were

included in the study (mean age 33610; 4 males, 6 females).

Patients were referred to clinicians specialized in EMDR

treatment (AV, GL, RR, IF) on the basis of the presence of major

psychological trauma. Although all patients were clinically

diagnosed as suffering from PTSD, due to logistics and patients’

refusal to long and elaborate procedures, no categorical diagnosis

could be made according to DSM-IV-TR criteria. Traumas

consisted in sexual abuse (5), grief and loss trauma (3), abortion

related trauma (1) and severe physical abuse (1) and EMDR

sessions focused on these specific life events. Ten healthy subjects

comparable for age and gender (mean age 3767; 5 males, 5

females) and aware of the study agreed to participate and to act as

controls of their own free will. In all of them the index trauma

chosen was the one with the highest impact on their memories.

The major distinction between patients and controls was the lack

of trauma-related symptoms in the latter group. Exclusion criteria

included a track record of clinically diagnosed psychiatric

disorders and a score of the psychological response to the stressful

index trauma (Impact of Event Scale total score, intrusion +avoidance) ,26, i.e. less than a moderate psychological response

to trauma. Prior to entering the study, all participants were

informed of the procedures and asked to subscribe to the

Declaration of Helsinki.

Study DesignThe study was entirely carried out in the therapy room of a

private clinic to which all patients were referred for treatment. The

room was quiet, light and airy and clinicians and patients, as well

as controls, were comfortable enough to establish a therapeutic

alliance. During the first session the clinician confirmed the

presence of a major psychological trauma and the persistence of

the related symptoms over time. All subjects were asked to record

as a digital file the autobiographical script of their traumatic

experience. After some days they returned to the therapist for the

first EMDR session (T0). Before the session started in the presence

of a trained psychologist (GN) all subjects filled in 3 self-

administered neuropsychological checklists whose completion

required about 30 minutes. They were then invited to walk into

the therapy room where the EEG cap was positioned.

EEG recording was continuously performed while the patients

were:

– at rest with eyes open and closed;

– listening to the script with eyes closed;

– during a second period with eyes closed;

– during EMDR therapy;

– during a final period of rest.

The same protocol was repeated during the last EMDR session

(T1), after the patient completely processed the trauma and

reported no disturbance with Subjective Unit of Distress

(SUD) = 0, Validity of Cognition (VOC) = 7 and clear Body Scan

(Figure 1). A clinical follow-up of two years was then performed

with all patients.

Control subjects underwent the same therapeutic protocol and

neuropsychological assessments as patients but the EEG recording

of the script and of the whole EMDR session were performed only

on one occasion, right after the initial neuropsychological

assessment (T0).

EMDR ProcedureAt the beginning of EMDR sessions patients and controls were

asked to focus on the primary elements of the traumatic memories

while at the same time following a "dual stimulation" using

bilateral ocular stimulation (BS) lasting usually 30 seconds and

entailing about 30 complete horizontal left-right-left eye move-

ments each. Progressive changes after BS sets reflect reprocessing

of the memory, until patients are able to engage in the recollection

of the event with no disturbing emotions and with positive and

constructive perspectives about themselves, showing desensitiza-

tion and experience adaptive resolution. Once the memory of the

traumatic event has been reprocessed, the EMDR protocol is

applied to recent triggers and to future anxiety provoking or

avoidance situations. Treatment will be completed as soon as past,

present and future trauma-related issues are addressed. Treatment

completion is usually associated with post-traumatic symptoms

reduction.

Treatment’s Eight PhasesPhase one is devoted to history taking. During phase one the

clinician assesses symptoms and makes a diagnosis. At this time the

patients’ readiness for EMDR is evaluated and a treatment plan is

carried out. Patients along with the therapist identify possible

EMDR processing targets. During phase two the therapist ensures

that patients are provided with adequate resources for handling

emotional distress and good coping skills. Patients are then

prepared to start processing traumatic material, by explaining the

method and showing BS, while focusing on a positive memory

(safe place exercise). From phase 3 through 6, a target is identified

and processed using the EMDR protocol. These phases involve

patients identification of the most vivid visual image related to the

memory (if available), a positive and a negative belief about the

self, related emotions and body sensations. In the desensitization

phase (Phase 4) patients are instructed to focus on the image,

negative belief and body sensations while simultaneously moving

their eyes back and forth following the therapist’s fingers as they

move across their field of vision for 20–30 seconds or more. This is

repeated numerous times throughout the session. When patients

report no distress related to the targeted memory, the clinician asks

them to think of their preferred positive belief and to focus on the

EEG Monitoring during EMDR Therapy

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incident, while simultaneously engaging in further sets of eye

movements. After several sets, patients generally report increased

confidence in this positive belief. The therapist checks the patients’

body sensations. If there are negative sensations, these are

processed as above. If there are positive sensations, they are

further enhanced. In the closure phase (phase 7), the therapist

instructs the patients how they should focus their attention after

the session and ask them to keep a weekly log and to write down

any related material that may arise. The therapist finally reminds

the patients of the self-calming activities that were mastered in

phase two. The next session begins with phase eight, i.e. reviewing

the work done and checking whether results are maintained from

the previous session.

Self-administered ChecklistsIES [17] is a 15-item checklist used to measure the psycholog-

ical response to stressful or traumatic life events during the

previous week. It specifically tackles the areas of intrusion (7-items

subscale) and avoidance (8-items subscale) as key features of

dysfunctional psychological adaptation following traumas. Scores

above 26 are regarded as clinically significant.

BDI [18] is a 21-item self-report measure containing items

related to the cognitive, affective as well as somatic symptoms of

depression. Items are rated between 0, not at all, and 3, severely,

in terms of how much they have bothered patients in the previous

week. Scores above 18 indicate moderate to severe depressive

symptoms.

SCL-90 R [19] is a 90-item self report symptom inventory used

as a measure of psychological problems assessing the frequency of

a broad range of symptoms of psychopathology. Patients rate the

90 items using a 5-point scale (1 = no problem to 5 = very severe)

to measure the extent to which they have experienced the

shortlisted symptoms over the last 7 days. The SCL-90-R has also

3 global indexes: the Global Severity Index (GSI) measures the

extent or depth of the individual’s psychiatric disturbance; the

Positive Symptom Total (PST) counts the total number of

questions rated above 1 point; and the Positive Symptom Distress

Index (PSDI) represents the intensity of symptoms.

Paired and un-paired t-tests were performed to compare the

scores of IES, BDI, SCL-90-R between patients pre- and post-

EMDR treatment and patients to controls, respectively.

EEG ProcedureEEG acquisition. Thirty-seven-channel EEG was recorded

using a pre-cabled electrode cap (Bionen, Florence, Italy). A

horizontal electro-oculographic (H-EOG) channel, recorded from

two electrodes at the outer canthus of each eye, was used to

monitor eye movements of BS. The electrodes cup montage

required approximately 20 minutes and was well tolerated by

subjects. Electrode impedances were kept less than 10 KV. The

signal was amplified by 40-channel EEG device (Galileo MIZAR-

sirius, EBNeuro, Florence, Italy) and acquired with GalNT

software. Data were collected with a sampling rate of 256 Hz

and with hardware EEG filters of High-Pass at 0.099 Hz and Low-

Pass at 0.45 SR (0.456256 Hz = 115.2 Hz).

Preprocessing. Data were exported to EDF using NPX Lab

2010 (www.brainterface.com). In both patients and controls while

the script recordings were fully exported, in the EMDR arm we

segmented and exported only the BS periods (eliminating,

arbitrarily, the first four and the last two eye movements), creating

files of 180 seconds each with concatenated/merged periods of BS.

Data were analyzed in the EEGLAB environment (http://www.

sccn.ucsd.edu/eeglab/index.html) a collection of scripts running

under Matlab 7.7.0 R2010a (Mathworks Inc., Natick, MA). After

visual inspection and manual elimination of paroxysmal artifact

periods, artifact non-cerebral source activities (eye blinks and

movements, cardiac and muscle/electromyographic activity) were

identified and rejected using a semiautomatic procedure based on

Independent Component Analysis [20].

Electrical Source Imaging (ESI). To compute the intrace-

rebral electrical sources underlying EEG activity recorded at the

scalp we used the exact low resolution brain electromagnetic

tomography (eLORETA) software (http://www.uzh.ch/keyinst/

loreta.htm). Computations were made in a realistic head model

[21], using the Montreal Neurological Institute (MNI; Montreal,

Quebec, Canada) MNI152 template, with the three-dimensional

solution space restricted to cortical gray matter and hippocampi,

Figure 1. Study design.doi:10.1371/journal.pone.0045753.g001

EEG Monitoring during EMDR Therapy

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as determined by the probabilistic Talairach atlas [22]. The

intracerebral volume (eLORETA inverse solution space) is

partitioned in 6239 voxels at 5 mm spatial resolution (i.e., cubic

elements of 56565 mm). Anatomical labels as Brodmann areas

are also reported using MNI space, with correction to Talairach

space [23]. We calculated eLORETA images corresponding to the

estimated neuronal generators of brain activity within each band

[24]. The ranges of the frequency bands were as follows: delta (d),

1.5–4 Hz; theta (h), 4–8 Hz; alpha (a), 8–12 Hz; beta 1 (b1), 12–

20 Hz; beta 2 (b2), 20–30 Hz; gamma (c), 30–45 Hz.

Statistics. eLORETA software package was used to per-

form ESI statistical analyses. The methodology used was non-

parametric randomization statistics (Statistical non-Parametric

Mapping, SnPM) [25]. A second level of non-parametric

analysis, the exceedence proportion tests evaluated the signifi-

cance of activity based on its spatial extent, obtaining clusters of

supra-threshold voxels.

Between-group comparisons of the eLORETA current density

distribution were performed using a statistical analysis based on

voxel-by-voxel log of F ratio test with 5000 randomizations. The

results corresponded, for each band, to maps of log-F-ratio

statistics for each voxel, for corrected p,0.05. Significant

activations at the exceedence proportion tests with a p value

,0.01, F value over 2 z-score and a minimum cluster of voxels

major than 27 (an intracerebral volume cube with an edge of

15 mm) within a hemisphere for single Broadmann Area (BA)

were accepted.

Electrical source functional connectivity. Functional con-

nectivity analysis was performed by the ‘‘whole-brain Brodmann

areas (BAs)’’ approach, using the anatomical definitions of 84 BAs

provided by eLORETA software package and based on the

Talairach Daemon (http://www.talairach.org/). Pairs of BAs were

analyzed using the values of single voxels with the highest F-ratio

value at the centroid of each BA. To test interregional functional

correlations between any pair of BAs lagged phase synchronization

(LPS), index of physiological lagged connectivity and decomposing

connectivity into instantaneous and lagged components, was used

[26,27]. It defines the phase synchronization between two signals

in the frequency domain based on normalized Fourier transforms

after partialling out the instantaneous, zero-lag contribution

resulting from non-physiological effects or intrinsic artifacts.

Hence, this measure is thought to contain physiological connec-

tivity information only.

Since no significant correlation was found for any of the 42

pairs, we selected 21 BAs (9, 10, 11, 17, 18, 19, 20, 23, 24, 25, 28,

30, 31, 32, 33, 34, 35, 36, 37, 46, 47), bilaterally, and repeated the

analyses without obtaining any significant result. Finally we chose

an a priori approach further reducing the number of tested regions

to the clusters in which for each group comparison significant

differences were found. The latter analyses were performed

averaging for each of the six EEG bands, the LPS values in all

voxels within a sphere of 15 mm of radius around the one with

maximal intensity.

Statistical comparisons were carried out using non-parametric

randomization techniques with correction for multiple compari-

sons.

Correlation with neuropsychological scores. To evaluate

the association between connectivity measures and neuropsycho-

logical variables, the LPS values of the pairs of clusters found to

have significantly changed were correlated to the scores of IES-

total, BDI total and SCL-90R-PSDI, yielding r, r2 and p values

corrected for multiple comparisons.

Results

Self-administered ChecklistsIn all patients after 3 to 8 EMDR sessions (mean 5) symptoms

related to the traumatic event disappeared and SUD and VOC

scores reached the normal values of 0 and 7 respectively. All

patients were still symptoms-free after 2 years of follow up. Scores

of IES, BDI and SCL-90-R were significantly different between

patients and controls at T0 (Table 1) and decreased significantly in

patients at T1 (Table 2).

EEGPatients vs. controls. During the script a significantly higher

cortical activation was found in patients’ bilateral orbito-frontal

cortex (OFC, BAs 11–47) and anterior cingulate cortex (ACC, BAs

24-25-32-33) for almost all frequencies between 1.5 and 20 Hz

(Table 3). Significantly higher bilateral activation was also found

for delta and theta bands bilaterally in parahippocampal gyri

(PHG, BAs 28-34-35-36) and for theta band in bilateral posterior

cingulate cortex (PCC, BAs 23-30-31) (Table 3; Figure 2). During

BS patients showed a higher cortical activation in left OFC, rostral

prefrontal cortex (rPFC, BA 10) and ACC for most of the bands

(Figure 3). Significantly higher activations in patients were also

found for some bands in PHG and PCC (Table 3).

Patients at T1 vs. patients at T0. During the script listening

there was a significantly higher cortical activation in patients at T1

in right fusiform gyrus (FG, BAs 20-37) for bands up to 20Hz. A

higher activation was also recorded at T1 in visual cortex for delta

and theta bands (Figure 4). During BS a significantly higher left

FG activation was found at T1 for all but theta bands (Table 3). In

this comparison a significantly higher activation was found at T0

as compared to T1 in rPFC, mainly on the left, and in right visual

cortex (Figure 5) in the frequencies between 3 and 20Hz.

Functional connectivity. At connectivity analysis a signifi-

cantly decreased pair-wise interaction as expressed by LPS

between left VC and right FG was found in patients at T1 as

compared to T0 during the script listening in the theta band.

Significantly decreased functional connectivity was also found in

patients in the gamma band during bilateral ocular stimulation in

comparison with controls in two pair-wise interactions: left PFC

and left PCC; left ACC and left PCC.

Correlation with neuropsychological scores. The scores

of the neuropsychological tests in patients were not only consistent

Table 1. Pre EMDR treatment: mean (SD) and statisticallysignificant differences in IES, BDI and SCL-90-R scores inpatients vs controls.

Patients(N = 10)

Controls(N = 10) T p

IES/pre/TOTAL 40.8 (15.9) 2 (3.1) 7.543 0.000

IES/pre/intrusion 21.1 (9.8) 1 (2.2) 6.297 0.000

IES/pre/avoidance 19.7 (7.7) 1 (1.3) 7.536 0.000

BDI/pre/TOTAL 23.9 (10.1) 1.6 (2.2) 6.795 0.000

BDI/pre/cognitive 15.7 (8.1) 0.70 (1.3) 5.799 0.000

BDI/pre/somatic 8.2 (3.3) 0.90 (1.3) 6.416 0.000

SCL-90-R/pre/PST 59.6 (20.2) 6.2 (6.35) 7.956 0.000

SCL-90-R/pre/PSDI 2.11 (.53) 0.82 (.61) 4.989 0.000

SCL-90-R/pre/GSI 1.49 (.65) 0.80 (.80) 6.293 0.000

doi:10.1371/journal.pone.0045753.t001

EEG Monitoring during EMDR Therapy

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with symptom remission as assessed clinically and by SUD and

VOC but they also correlated significantly with LPS in the pair-

wise interactions found to be significantly changed. The patho-

logical pre-EMDR and normalized post-EMDR scores of IES

total, BDI total and SCL-90-R PSDI, taken as a continuum, showed

a significantly positive correlation in theta band with the LPS

values of the pair-wise interaction between left VC and left FG

during script listening in patients at T1 vs T0. Negative

correlations in the gamma band between LPS values and the

same neuropsychological tests scores were found for the other two

pair-wise interactions found to be significantly decreased during

BS in patients as compared to controls: left PFC vs left PCC; and

left ACC vs left PCC (Table 4).

Discussion

The first relevant result of the study was the ability to perform

an on-line monitoring of the cortical firing occurring during

EMDR therapy by means of the EEG, more specifically during

bilateral ocular stimulation. For the first time, maximal brain

activations associated with the therapeutic actions envisaged by the

EMDR protocol could be outlined and represented on the cortical

surface. To the best of our knowledge this is also the first time

psychotherapy is monitored and dynamically represented by

functional imaging throughout its entire duration. The logistic

and technical effectiveness of such complicated methodology

carried out by psychotherapists, psychologists, psychiatrists and

EEG technicians, all at the same time, provided the opportunity of

performing the experiments in a totally patient-friendly environ-

ment, i.e. in a comfortable private practice therapy room, avoiding

possible biases resulting from physical and psychological discom-

fort for the patient due to an unfriendly examination environment

[28].

Following successful EMDR therapy, the main neurobiological

finding of the study was the shift of the maximal cortical firing,

during both autobiographic script listening and BS, from

prefrontal and limbic regions at T0 to fusiform and visual cortex

at T1 (Figure 4 and 5, respectively). Also when compared to

asymptomatic normal subjects the reliving of the major traumatic

event caused in patients a significantly higher bilateral limbic firing

during the script (Table 3; Figure 2) and a more leftward oriented

limbic activation during BS (Figure 3). The latter finding might be

Table 2. Pre vs post EMDR treatment: mean (SD) andstatistically significant differences in IES, BDI and SCL-90-Rscores in patients.

Patients (N = 10) T p

IES/pre/TOTAL vs IES/post/TOTAL 40.8 (15.9) vs 12.8 (12) 6.386 0.000

IES/pre/intrusion vs IES/post/intrusion 21.1 (9.8) vs 6.6 (6.6) 5.7 0.000

IES/pre/avoidance vs IES/post/avoidance 19.7 (7.7) vs 6.3 (5.9) 5.448 0.000

BDI/pre/TOTAL vs BDI/post/TOTAL 23.9 (10.1) vs 9.5 (9.5) 4.003 0.003

BDI/pre/cognitive vs BDI/post/cognitive 15.7 (8.1) vs 6.7 (7.1) 3.085 0.013

BDI/pre/somatic vs BDI/post/somatic 8.2 (3.3) vs 2.8 (2.6) 4.92 0.001

SCL/pre/PST vs SCL/post/PST 59.6 (20.2) vs 37.7 (19.7) 4.948 0.001

SCL/pre/PSDI vs SCL/post/PSDI 2.11 (.53) vs 1.41 (.46) 3.625 0.006

SCL/pre/GSI vs SCL/post/GSI 1.49 (.65) vs 0.66 (.52) 4.131 0.003

doi:10.1371/journal.pone.0045753.t002

Table 3. Regions in which significant differences were found between different conditions and groups.

BA d h a b1 b2 c

left right left right left right left right left right left right

SCRIPT PATIENTS –CONTROLS

OFC 76 35 65 29 70 27

ACC 40 38 47 36 44 35

PHG 35 56 48 42 39

PCC 34 58

BS PATIENTS - CONTROLS OFC 59 77 113 155

rPFC 72 48 72 46 91 97

ACC 34 30 39 44

PHG 33 37 41 36 32

PCC 29 34 32 56

SCRIPT PATIENTS T1 –PATIENTS T0

FG 48 104 50 134

VC 212 46 41

BS PATIENTS T1 –PATIENTS T0

FG 108 81 88 127 115

BS PATIENTS T0 –PATIENTS T1

rPFC 37 40 27 44

VC 33 42 43

BS = bilateral ocular stimulation during EMDR therapy; d= delta, 1.5–4 Hz; h= theta, 4–8 Hz; a= alpha, 8–12 Hz; b= beta 1, 12–20 Hz; b2 = beta 2, 20–30 Hz; c= gamma,30–45 Hz; OFC = orbito-frontal cortex (BAs 11–47); ACC = anterior cingulate cortex (BAs 24-25-32-33); PHG = parahippocampal gyrus (BAs 28-34-35-36); PCC = posteriorcingulated cortex (BAs 23-30-31; FG = fusiform gyrus (BAs 20–37); VC = visual cortex (BAs 17-18-19); rPFC = rostral prefrontal cortex (BA 10). For significant comparisonsthe number of voxels in each cluster is reported for each band and each hemisphere.doi:10.1371/journal.pone.0045753.t003

EEG Monitoring during EMDR Therapy

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related during BS to the guided attempt to encode unelaborated

emotional material, activating preferentially left rPFC [29].

The significantly higher activation found in patients during the

BS at T0 compared to T1 in rPFC (Figure 5) confirms the leftward

differences found during the same phase in patients as compared

to controls (Figure 3). Prefrontal activation is associated with

evaluation of self-generated material [30] being anterior cingulate

cortex the point of integration of emotional information involved

in the regulation of affect [31] as well as a key substrate of

conscious emotional experience monitoring information with

affective consequences. Rostral PFC as part of the limbic system

is thought to be involved in processes concerning the emotional

value of incoming information and to be critically implicated in

functions altered in psychic trauma response. Its activation upon

emotional induction is considered to represent the neurobiological

correlate of the affective valence of the stimulus [32]. Moreover,

episodic memory retrieval is known to activate PFC [33], and a

close relationship between autobiographical/episodic memory, the

self and the involvement of PFC was described [34]. PFC has also

been found to be activated while suppressing unwanted memories

[35] and was found by near infrared spectroscopy to be activated

during trauma recall before EMDR therapy [36]. All these

functions may be exaggerated in patients before EMDR therapy in

which the self-referential emotional contents cause an activation in

rPFC larger than in normal individuals or in the patients after

having processed the traumatic event.

One relevant neurobiological effect of EMDR in patients was

represented by the differences found between the cortical

activation at T0 as compared to T1 during script listening

(Figure 4). In this comparison we found at T1 a significant increase

of the EEG signal in right FG as well as in right visual cortex (VC).

These changes suggest a better cognitive and sensorial (visual)

processing of the traumatic event during the autobiographic

reliving after successful EMDR therapy with a preferential

activation moving from the emotional fronto-limbic cortex (at

T0) towards the associative temporo-occipital cortex (at T1). Once

the memory retention of the traumatic event can move from an

implicit subcortical to an explicit status different cortical regions

participate in processing the experience. On the other hand FG is

implicated in the explicit representation of faces, words and

abstract thoughts [37] and its prevalent activation after successful

EMDR therapy might be associated with an elaboration at higher

cognitive level of the images related to the event.

As found in the script analysis, FG showed a higher activation

also during BS at T1. Interestingly, in our patients these

comparisons showed different outcomes with a clear lateralization

towards the left hemisphere during BS (Figure 5) and on the right

side during the script listening (Figure 4). According to the

emotional asymmetry theory the right hemisphere is dominant

over the left for emotional expressions and perception. Further-

more, both hemispheres function as somewhat of a functional unit

and an increased activation in one of them will result in an

inhibition in the contralateral one. The prominent activation

Figure 2. SCRIPT: PATIENTS - CONTROLS (theta band). Cortical representation of the cluster of voxels in which the EEG signal showedsignificant differences between groups. Activation increases exceeding a p value , 0.01 and an F value over 2 z-score are depicted by red color scale.Top row left: lateral view of left hemisphere; Top row middle: lateral view of right hemisphere; Top row right: view from below; Bottom row left:medial view of left hemisphere; Bottom row middle: medial view of right hemisphere; Bottom row right: transversal section at prefrontal cortex levellevel (z = 5). Regional details are presented in Table 3.doi:10.1371/journal.pone.0045753.g002

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found during BS at T1 in association areas in left hemisphere

might then correspond to a cognitive processing of traumatic

memories reaching the explicit state after successful EMDR

therapy associated to a significant restraint of negative emotional

experiences. The left hemisphere has also an important role in

explicating emotions and left FG was also found to be activated

during tasks implying episodic memory and memory retrieval

associated with attentional control [37].

The differential neuronal firing at T0 in patients as compared to

control subjects (Figure 2 and 3) not only highlighted the

emotional component of the trauma retrieval when patients were

still symptomatic but also ruled out the possibility that these

regions were activated merely due to the reliving of the index

event. Furthermore in both script and BS patients activated more

than controls PHG and ACC, being the latter the neural link of

the former with PFC. The primary difference between patients

and controls was not due to the nature of traumas but to the lack

of symptoms in the latter. Physical and/or psychological traumas

cause anxiety states based not only on severity but also on

personality, on life-time trauma load and probably on genetic

factors associated to each individual person.

After progressively reducing the number of investigated regions

out of the clusters resulting significantly different in the group

comparisons, interregional connectivity changes reported while

reliving of the traumatic event, representing the variations in brain

activity networking upon different conditions, were found in three

cluster pairs. The loss of functional connectivity between left VC

and FG found in patients at T1 as compared to T0 during the

script listening was associated with the disappearance of symptoms

and speaks in favor of disconnection of a pathological visual

network after successful EMDR therapy. At this stage, as an effect

of successful trauma elaboration, the visual images of the event are

processed and stored in primary and associative visual cortex and

likely decoupled from the emotional memory of faces and bodies

linked to the event, typically processed by FG. Moreover,

affectively valenced stimuli were shown to prompt event-related

synchronization in posterior brain regions in the theta frequency

band [38]. Such synchronization might have disappeared once the

images of the traumatic event lost their emotional meaning.

The findings of decreased pair-wise interactions between PFC,

ACC and PCC found in patients as compared to controls during

BS show that the functional connectivity during trauma relieving

and involving three important frontal regions was not present in

patients. This underscores the pathological nature of the changes

occurring in post-traumatic conditions in the limbic system and

the central role of the latter in properly processing negative

autobiographical events. Event-related activity in gamma band

was observed in healthy volunteers in ACC and left PFC upon

exposition to emotional stimuli [39], suggesting that gamma

activity in PFC may be modulated by emotional processing in

ACC. Furthermore gamma band seems to reflect short distance

synchrony [40].

The relative low number of significant pairs-wise interactions

found in the present study is probably due to the limited number

Figure 3. EMDR BS: PATIENTS - CONTROLS (gamma band). Cortical representation of the cluster of voxels in which the EEG signal showedsignificant differences between groups. Activation increases exceeding a p value ,0.01 and an F value over 2 z-score are depicted by red color scale.Top row left: lateral view of left hemisphere; Top row middle: lateral view of right hemisphere; Top row right: view from below; Bottom row left:medial view of left hemisphere; Bottom row middle: medial view of right hemisphere; Bottom row right: transversal section at prefrontal cortex levellevel (z = 5). Regional details are presented in Table 3.doi:10.1371/journal.pone.0045753.g003

EEG Monitoring during EMDR Therapy

PLOS ONE | www.plosone.org 7 September 2012 | Volume 7 | Issue 9 | e45753

of investigated subjects (and hence to lesser statistical power). The

constraint to restrict the amount of regions from the 84

eLORETA default ones to the clusters resulting significant in

group comparisons was due to multiple comparisons corrections,

cutting down dramatically on the significance of each analysis.

When more patients and controls are available a dedicated study

aiming specifically at investigating functional connectivity will be

possible.

Comparing our findings to previous studies investigating

psychological traumas [41], significantly higher activations in

OFC and rPFC in patients during script were found by some

[13,42–44], but not by other authors [45,46]. SPECT studies have

also investigated the effect of psychotherapies and pharmacologic

treatment on CBF reporting both increases and decreases

distributed throughout the whole cortex [11,13,47,48]. Functional

studies in psychological trauma employ different methodologies

varying from analyzing resting brain activity to the implementa-

tion of stimuli and active tasks, including scripts. Moreover,

patients with broad trauma spectra and types are recruited

resulting in different brain activation patterns. Due to this

heterogeneity, comparing data across studies is difficult especially

when different methodologies are implemented as in the case of

this pioneering EEG study.

All bands showed significantly different changes across the four

performed comparisons especially at frequencies between 1.5 and

20 Hz (Table 3). The significant differences in theta frequency

were mostly found during the autobiographical script analyses

(Table 3; Figure 2 and 4). Hippocampal theta rhythm is implicated

in episodic memory [49] and memory formation and retrieval [50]

and has been found to correlate with neuronal firing in frontal

cortex [51,52]. Furthermore increased theta activity localized in

hippocampus was found in one of the few studies investigating

EEG in PTSD [53] supporting the evidence of its role in

modulating emotional memories.

Another interesting finding of the study is the significant

difference in gamma band between patients and controls during

BS (Table 3, Figure 3). Such difference, localized in frontal cortex

and PHG during the effort to encode unprocessed emotional

material, is consistent with previous studies on gamma synchro-

nicity in which neuronal firing in frontal cortex was associated

with behaviorally relevant sensory information and highly alert

brain states [54]. On the other hand, attention was associated with

reduced alpha rhythms [55] and the latter negatively correlated

with behavioral performances in non-human primates [56] having

also an active role in inhibiting unattended information in

attentional tasks [57]. The finding of a significantly lower alpha

band activity in frontal cortex at T1 (Figure 5) supports the

hypothesis that after trauma processing with EMDR the traumatic

event per se will be under control through a more attentive

cognitive-associative modes. In this respect also the prominent

beta band activation in limbic regions (OFC, rPFC, ACC, PHG

and PCC) can be interpreted as increased selective attention and

perception of the index trauma in patients as compared to controls

[58].

Figure 4. SCRIPT: PATIENTS T1 - PATIENTS T0 (theta band). Cortical representation of the cluster of voxels in which the EEG signal showedsignificant differences between conditions. Activation increases exceeding a p value ,0.01 and an F value over 2 z-score are depicted by red colorscale. Top row left: lateral view of left hemisphere; Top row middle: lateral view of right hemisphere; Top row right: view from below; Bottom row left:medial view of left hemisphere; Bottom row middle: medial view of right hemisphere; Bottom row right: transversal section at temporal cortex level(z = 210). Regional details are presented in Table 3.doi:10.1371/journal.pone.0045753.g004

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Delta waves were significantly higher in patients as compared to

controls and in patients at T1 as compared to T0 in all regions

involved in the EMDR related changes (Table 3). Their increase

in association with BS can tentatively be ascribed to the oscillation

caused by such slow-wave-sleep-like stimulus [59] and their

increase in frontal cortex of patients as compared to controls

might be related to thought processes under unusual conditions

[60].

A recent theory postulates that traumatic memories are retained

in amygdalar synapses due to powerful electric signals over-

potentiating alpha-amino-3-hydroxy-5-methyl- 4-isoxazole

(AMPA) receptors. During slow wave sleep (SWS) this would

prevent their merging with the cognitive memory trace via

anterior cingulate cortex (for review see [59]). Animal studies have

demonstrated that a low-frequency tetanic stimulation using one to

five pulses per second can cause in the synapses of the basolateral

Figure 5. EMDR BS: PATIENTS T1 - PATIENTS T0 (alpha band). Cortical representation of the cluster of voxels in which the EEG signal showedsignificant differences between conditions. Activation increases exceeding a p value ,0.01 and an F value over 2 z-score are depicted by red colorscale; activation decreases are depicted by blue color scale. Top row left: lateral view of left hemisphere; Top row middle: lateral view of righthemisphere; Top row right: view from below; Bottom row left: medial view of left hemisphere; Bottom row middle: medial view of right hemisphere;Bottom row right: transversal section at primary visual cortex level (z = 15). Regional details are presented in Table 3.doi:10.1371/journal.pone.0045753.g005

Table 4. Correlations between Lagged Phase Synchronization (LPS) indexes and psychometric variables.

Changed pair-wise interactions vsneuropsychological tests r r2 p

SCRIPT T1 vs T0 (theta band) left VC – right FG vs IES 0.531 0.282 0.016

left VC – right FG vs BDI 0.505 0.255 0.023

left VC – right FG vs PSDI 0.484 0.235 0.030

EMDR patients vs controls (gamma band) left PFC – left PCC vs IES 20.666 0.443 0.001

left PFC – left PCC vs BDI 20.594 0.353 0.006

left PFC – left PCC vs PSDI 20.550 0.302 0.012

left ACC – left PCC vs IES 20.644 0.415 0.002

left ACC – left PCC vs BDI 20.567 0.322 0.009

left ACC – left PCC vs PSDI 20.493 0.243 0.027

doi:10.1371/journal.pone.0045753.t004

EEG Monitoring during EMDR Therapy

PLOS ONE | www.plosone.org 9 September 2012 | Volume 7 | Issue 9 | e45753

tract of the amygdale a depotentiation of AMPA receptors

proportional to the stimulation frequency and extinguishing the

traumatic memories [61].

Such stimulus is similar to the one administered during EMDR

sessions (about 2 Hz) and the pathophysiological mechanism of the

therapy might be related to the slowing of the depolarization rate

of neurons in the limbic system elicited by BS. This in turn would

result in the emotional memories pathologically confined in the

amygdale moving to higher brain centers and being fully processed

[59]. At macroscopic level, our findings (hyperactivation of

parahippocampal gyrus and limbic cortices at T0 in both BS

and script listening) seem to support such hypothesis even if in

humans functional studies focused on neuronal firing, finer spatial

identification and time resolution are needed to better investigate

this fascinating issue.

According to the Adaptive Information Processing theory [62]

when a traumatic event occurs, information processing may be

incomplete, probably due to the fact that strong negative feelings

or neurobiological reactions interfere with it. This prevents the

forging of associative connections of memory with other networks

and memory is dysfunctionally stored. During an EMDR session

memory distressing components are linked to more adaptive

information existing in the neural networks and therefore memory

desensitization and reprocessing take place, thus contributing to

symptom reduction and ultimately remission.

The assessment of severity and persistence of trauma related

symptoms is of paramount importance. IES and BDI are

commonly administered pre- and post-treatment as measures of

outcome and this approach is particularly evident in studies on

effectiveness of psychotherapy for traumatised patients [9,63].

The dramatic decrease of IES from moderate impact to sub-cut-

off scoring was such for both intrusion and avoidance subscales

indicating the efficacy of EMDR sessions on both components.

The same held true for BDI in which scores moved from moderate

depression to sub threshold values between minimal and mild

depression ranges for both cognitive and somatic components.

We found significant positive correlations between the func-

tional connectivity changes (as expressed by lagged phase

synchronization values) in patients at T1 as compared to T0 in

VC and FG and the scores of neuropsychological tests during

script listening and negative correlations of the same scores and

some regions of the frontal and parietal limbic system in which

reciprocal connectivity changed significantly (PFC, ACC and

PCC) during BS when comparing patients and controls (see

Table 4).

The different directions of the correlations are due to the fact

that LPS represented in the former case a decreased connectivity

between patients at T1 as compared to patients at T0 (lower LPS,

lower neuropsychological scores) whereas in the latter case control

subjects showed higher connectivity (higher LPS, lower neuropsy-

chological scores).

Such correlations highlight the association between three

important dimensions of the pathological and diagnostic processes

(i.e. functional changes, neuropsychological assessment and

clinical status) and confirm the neurobiological ground and effects

of EMDR therapy. Statistical significance was achieved in the

correlations of tests scores of IES total, BDI total and SCL-90R-

PSDI with all the investigated pair-wise interactions confirming

the role of the above neuropsychological tests in the diagnosis and

clinical assessment of post-traumatic conditions. In the future more

studies with a larger number of subjects are needed to highlight the

correlations between such scores and other regions, but more

importantly to identify the sites of neural representations and/or

processing of the above constructs under post-traumatic conditions

[64].

EMDR sessions, seemed also to spread positive effects on a

general reduction of psychiatric symptoms associated with the

posttraumatic condition, quite the rule in individuals who have

experienced multiple and repeated traumas [65]. In this respect,

the literature shows a compelling evidence of what Bremner [66]

has described as ‘‘trauma spectrum psychiatric disorders’’ includ-

ing mild to severe depression and anxiety disorder [67,68]. Our

findings seem to follow this vein since in patients all three scores of

global index of distress of SCL-90-R were significantly changed

after EMDR therapy. The striking decrease in depression as

measured by the BDI and in the quantity and quality of symptoms

as measured by the SCL-90-R has to be regarded as a further

indication of EMDR treatment efficacy in tackling and amelio-

rating psychiatric disorders in the trauma spectrum.

One of the constraints of the study is the relatively small number

of investigated subjects. However numerousness lies in the

magnitude of the neuroimaging study in which the high costs

and the complicated methodologies limit the amount of subjects to

be studied. On the other hand recruitment of controls increased

the robustness of the results adding a between-subjects analysis to

the comparison of patients at T0 and T1. Finally, a systematic and

exhaustive discussion of all differences found in each EEG band

(Table 3) was beyond the scope of the present study and we have

deliberately confined the discussion to some of the most relevant

results.

ConclusionsOur findings point to a highly significant activation shift

following EMDR therapy from limbic regions with high emotional

valence to cortical regions with higher cognitive and associative

valence. This suggests a strong neurobiological rationale of

EMDR, thus supporting its efficacy as an evidence- based

treatment for trauma. On the other hand the pathophysiological

changes occurring during EMDR psychotherapy were monitored

on-line for the first time, confirming the validity of the proposed

EEG methodology and encouraging further studies with a larger

cohort of subjects.

Acknowledgments

The authors wish to thank Dr. Patrizia Cogolo for assisting in self-

administered checklists collection, Mrs. Emanuela Enrico for English

editing, Dr. Andrea Daverio for assisting in Figure preparation and Mr.

Manuel Abbafati for the valuable technical assistance.

Author Contributions

Conceived and designed the experiments: MP GDL GN CN MA AS.

Performed the experiments: MP GDL ARV LM GN GL RR IF. Analyzed

the data: MP GDL LM GN CN. Contributed reagents/materials/analysis

tools: GDL LM GN CN MA AS. Wrote the paper: MP GDL ARV GN

CN GL MA IF AS. Provided private practitioner room for the

experiments: ARV RR GL.

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